Immune Reconstitution

免疫重建

• 批准号: 10262110
• 负责人: Ronald Gress
• 金额: $ 224.14万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262110
• 关键词: Acute; Address; Aging; Allogenic; Area; B-Cell Development; B-Lymphocytes; Biology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCR4 gene; Cell Aging; Cell Compartmentation; Cell Cycle Regulation; Cell surface; Cells; Clinical; Clinical Trials; Complex; Development; Disease; Distal; Dose; FLT3 ligand; Female; Gene Expression; Genes; Glucose; Goals; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homeostasis; Human; Image; Immune; Immune system; Interleukin 7 Receptor; Interleukin-7; Investigation; Isotopes; Kinetics; Maintenance; Malignant Neoplasms; Marrow; Mediating; Memory; Multiprotein Complexes; Mus; Natural regeneration; Organ; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral; Phenotype; Population; Premature aging syndrome; Proliferating; Proteins; Publishing; Regulation; Research; Role; Sensitivity and Specificity; Series; Signal Transduction; Stromal Cells; T cell reconstitution; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TP53 gene; Therapeutic; Thymocyte Development; Thymus Gland; Transplantation; Work; base; cancer therapy; cell regeneration; chronic graft versus host disease; cytokine; experimental study; functional disability; immune reconstitution; interest; male; memory CD4 T lymphocyte; mouse model; neoplastic cell; notch protein; precursor cell; reconstitution; senescence; stem cells; thymocyte; uptake

The biology of reconstitution of T cell populations following acute loss remains incompletely characterized. Using murine models, we first identified two primary pathways of T cell immune reconstitution, the classic, thymic-dependent pathway, and a second, thymic-independent pathway. We then identified T cell surface markers which allowed identification, by phenotyping of reconstituted T cell populations, of the pathways which had given rise to them, and then applied this information to the characterization of T cell reconstitution in patients. This work showed an essential role for the thymus in regenerating CD4+ T cells quantitatively. CD8+ T cells can numerically be reconstituted by peripheral expansion for immune reconstitution, but both CD4+ and CD8+ T cells require thymic activity for maintenance or regeneration of repertoire diversity. These findings led in turn to a research emphasis on understanding mechanisms which control thymic function, and new treatments to treat cancer in the setting of a regenerating immune system. This work has progressed to the development of two new project areas of research -- one focused on points of regulation of thymus function and one on introducing agents into clinical trials. The work addressed in this project has also led to efforts in investigating IL-7 effects on the maturation of thymocytes. We have identified IL-7 as a negative regulator of thymopoiesis as well as being essential for thymocyte development. These dual roles are dose dependent and negative regulation at higher concentrations is mediated through control of Notch signaling -- which is central to T/B lineage commitment. At high doses, IL-7 favors B cell development and so turns the thymus towards a B cell-poietic organ. Additionally, we have worked to identify genes which might regulate the thymus and have characterized a gene called Tbata (previously SPATIAL) which is a negative regulator acting within the stromal cell compartment. It appears to exert its effect through control of cell cycle, specifically through regulation of the Nedd8 pathway. Recent results indicate that regulation of cell cycle by Tbata extends beyond Nedd8 and involves p53. This is due to involvement of the protein encoded by Tbata in a large multi-protein complex which controls gene expression. Interestingly, this may be reflected in differences of thymopiesis in female versus male mice. The difference is now clear from multiple experiments, and the mechanism is under investigation. Experiments are in progress to identify blockers of Tbata function that might have clincial applicability. The role of IL-7 as a possible regulator of thymus function was noted above; its role in peripheral homeostasis has been further investigated by characterizing IL-7 receptor regulation among T cell subsets. The work with IL-7 receptor modulation has shown a complex pattern of differential signaling regulation among subsets with the apparent effect of favoring the sustaining of primitive naive T cells. This is of special interest because it provides a basis for understanding how a single cytokine such as IL-7 can differentially regulate multiple distinct T cell subsets. Specifically, there is differential regulation between naive CD4 T cells and memory CD4 T cells. Differences in signaling distal to the receptor for IL-7 appear to mechanistically account for this differential regulation. We are now addressing the biology of signaling by the two primary homeostatic cytokines in the CD8 naive versus CD8 memory subsets in murine models and have found again differences at the level of T cell receptor turnover. These results are now published. We have also made the observation that in T cell immune reconstitution reliant on the thymus-independent pathway in humans, that such expansion results in premature aging of the T cells with resultant cellular senescence, a likely contributor to T cell functional impairment for years following transplant. Investigating the stem cell compartment in murine models, we showed that FLT3 ligand regulates thymic precursor cells and hematopoietic stem cells through interactions with CXCR4 and the marrow niche. Finally, a series of experiments using deuterated glucose to assess T cell subsets kinetics in the pathogenesis of chronic GVHD in murine models yielded information on such subsets and evolved into efforts to successfully image rapidly proliferating cells in that disease. This collaborative work has progressed to imaging of other rapidly proliferating cells, namely neoplastic cells. This imaging has sufficient sensitivity and specificity to be of clinical interest. It also may have therapeutic application in the treatment of disease by selective uptake of isotope based on proliferative activity.

急性损失后T细胞种群重建的生物学仍然没有完全表征。使用鼠模型，我们首先确定了T细胞免疫重建的两种主要途径，经典的胸腺依赖性途径和第二个胸腺独立途径。然后，我们确定了T细胞表面标记，通过表型来识别重组的T细胞种群，对引起它们产生的途径的途径，然后将此信息应用于患者中T细胞重建的表征。这项工作表现出胸腺定量再生CD4+ T细胞的重要作用。 CD8+ T细胞在数值上可以通过外周膨胀以进行免疫重建，但是CD4+和CD8+ T细胞都需要胸腺活性来维持或再生曲目多样性。这些发现又导致研究重点是理解控制胸腺功能的机制，以及在再生免疫系统中治疗癌症的新治疗方法。这项工作已发展为开发两个新的研究领域 - 一项侧重于调节百里香功能的点，另一个侧重于将代理引入临床试验中。该项目中涉及的工作还导致了研究IL-7对胸腺细胞成熟的影响的努力。我们已经将IL-7确定为胸腺甲基膜的负调节剂，并且对于胸腺细胞发育至关重要。这些双重作用是剂量依赖性，在较高浓度下的负调节是通过控制Notch信号传导介导的 - 这是T/B谱系承诺的核心。在高剂量下，IL-7有利于B细胞的发育，因此将胸腺转向B细胞繁殖器官。此外，我们还努力鉴定可能调节胸腺的基因，并表征了一个称为TBATA（以前空间）的基因，该基因是作用于基质细胞室内的负调节剂。它似乎通过控制细胞周期，特别是通过调节NEDD8途径来发挥作用。最近的结果表明，TBATA对细胞周期的调节延伸超过NEDD8，涉及p53。这是由于TBATA编码的蛋白质参与了控制基因表达的大型多蛋白质复合物。有趣的是，这可能反映在雌性小鼠与雄性小鼠的胸腺多发性差异中。现在，从多个实验中可以明显差异，并且该机制正在研究中。正在进行实验，以识别可能具有缩写适用性的TBATA功能的阻滞剂。上面指出了IL-7作为胸腺功能的可能调节剂的作用。通过表征T细胞亚群中IL-7受体调节的表征，进一步研究了其在外围稳态中的作用。 IL-7受体调制的工作显示了子集之间差异信号传导调节的复杂模式，其明显的效果有利于维持原始的幼稚T细胞。这是特别感兴趣的，因为它为理解单个细胞因子（例如IL-7）如何差异调节多个不同的T细胞子集提供了基础。具体而言，幼稚的CD4 T细胞和记忆CD4 T细胞之间存在差异调节。 IL-7受体远端信号传导的差异似乎在机械上解释了这种差异调节。现在，我们正在解决鼠模型中CD8 NAIVE与CD8记忆集中的两个主要稳态细胞因子的信号传导生物学，并在T细胞受体更新水平上再次发现差异。这些结果现已发布。我们还观察到，在T细胞免疫重建中，依赖于人类的胸腺独立途径，这种扩展导致T细胞过早衰老，导致细胞衰老，这可能是在移植后多年导致T细胞功能障碍的原因。研究了鼠模型中的干细胞区室，我们表明FLT3配体通过与CXCR4和Marrow Liche的相互作用来调节胸腺前体细胞和造血干细胞。最后，一系列使用氘化葡萄糖在鼠模型中评估慢性GVHD发病机理的T细胞子集动力学的一系列实验产生了有关此类子集的信息，并演变为成功地形象地图对该疾病中快速增殖的细胞进行图像的努力。这项协作工作已发展为其他快速增殖细胞（即肿瘤细胞）的成像。该成像具有足够的敏感性和特异性，具有临床意义。它也可能通过基于增殖活性的同位素选择性吸收同位素来治疗疾病的治疗。